Prevalence and Clinical Implications of a β-Amyloid–Negative, Tau-Positive Cerebrospinal Fluid Biomarker Profile in Alzheimer Disease
Authors: Pontus Erickson, Joel Simrén, Wagner S. Brum, Gilda E. Ennis, Gwendlyn Kollmorgen, Ivonne Suridjan, Rebecca Langhough, Erin M. Jonaitis, Carol A. Van Hulle, Tobey J. Betthauser, Cynthia M. Carlsson, Sanjay Asthana, Nicholas J. Ashton, Sterling C. Johnson, Leslie M. Shaw, Kaj Blennow, Ulf Andreasson, Barbara B. Bendlin, Henrik Zetterberg, Michael Weiner, Paul Aisen, Ronald Petersen, Clifford R. Jack, William Jagust, John Q Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Leslie M. Shaw, Enchi Liu, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, Nigel J. Cairns, Erin Householder, Lisa Taylor Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Faber Kelley, Sungeun Kim, Kwangsik Nho, Zaven Kachaturian, Richard Frank, Peter J. J Snyder, Susan Molchan, Jeffrey Kaye, Joseph Quinn, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Beccera, Liberty Teodoro, Bryan M. M Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L Heidebrink, Joanne L Lord, Sara Mason, Colleen Albers, David Knopman, Kris Johnson, Rachelle S Doody, Javier Villanueva Meyer, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S Honig, Karen L Bell, Beau Ances, John C Morris, Maria Carroll, Sue Leon, Mark A Mintun, Stacy Schneider, Angela OliverNG, Randall Griffith, David Clark, David Geldmacher, John Brockington, Erik Roberson, Hillel Grossman, Effie Mitsis, Leyla deToledo-Morrell, Raj C Shah, Ranjan Duara, Daniel Varon, Maria T Greig, Peggy Roberts, Marilyn Albert, Chiadi Onyike, Daniel D’Agostino, Stephanie Kielb, James E Galvin, Dana M Pogorelec, Brittany Cerbone, Christina A Michel, Henry Rusinek, Mony J de Leon, Lidia Glodzik, Susan De Santi, P Murali Doraiswamy, Jeffrey R Petrella, Terence Z Wong, Steven E Arnold, Jason H Karlawish, David Wolk, Charles D Smith, Greg Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Oscar Lopez, MaryAnn Oakley, Donna Simpson, Anton Porsteinsson, Bonnie Goldstein, Kim Martin, Kelly Makino, M Saleem Ismail, Connie Brand, Ruth Mulnard, Gaby Thai, Catherine Mc Adams Ortiz, Kyle Womack, Dana Mathews, Mary Quiceno, Ramon Diaz Arrastia, Richard King, Myron Weiner, Kristen Martin Cook, Michael DeVous, Allan Levey, James Lah, Janet Cellar, Jeffrey Burns, Heather Anderson, Russell Swerdlow, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel Silverman, Po Lu, George Bartzokis, Neill Graff Radford, Francine ParfittH, Tracy Kendall, Heather Johnson, Martin Farlow, Ann Marie Hake, Brandy Matthews, Scott Herring, Cynthia Hunt, Christopher van Dyck, Richard Carson, Martha G MacAvoy, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging Yuek Robin Hsiung, Howard Feldman, Benita Mudge, Michele Assaly Past, Andrew Kertesz, John Rogers, Dick Trost, Charles Bernick, Donna Munic, Diana Kerwin, Marek Marsel Mesulam, Kristine Lipowski, Chuang Kuo Wu, Nancy Johnson, Carl Sadowsky, Walter Martinez, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A Sperling, Keith A Johnson, Gad Marshall, Meghan Frey, Jerome Yesavage, Joy L Taylor, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N Sabbagh, Christine M Belden, Sandra A Jacobson, Sherye A Sirrel, Neil Kowall, Ronald Killiany, Andrew E Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O Obisesan, Saba Wolday, Joanne Allard, Alan Lerner, Paula Ogrocki, Leon Hudson, Evan Fletcher, Owen Carmichael, John Olichney, Charles DeCarli, Smita Kittur, Michael Borrie, T Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M Carlsson, Steven G G Potkin, Adrian Preda, Dana Nguyen, Pierre Tariot, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W Scharre, Maria Kataki, Anahita Adeli, Earl A Zimmerman, Dzintra Celmins, Alice D Brown, Godfrey D Pearlson, Karen Blank, Karen Anderson, Robert B Santulli, Tamar J Kitzmiller, Eben S Schwartz, Kaycee M SinkS, Jeff D Williamson, Pradeep Garg, Franklin Watkins, Brian R Ott, Henry Querfurth, Geoffrey Tremont, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J Rosen, Bruce L Miller, Jacobo Mintzer, Kenneth Spicer, David Bachman, Elizabether Finger, Stephen Pasternak, Irina Rachinsky, Dick Drost, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Susan K Schultz, Laura L Boles Ponto, Hyungsub Shim, Karen Elizabeth Smith, Norman Relkin, Gloria Chaing, Lisa Raudin, Amanda Smith, Kristin Fargher, Balebail Ashok Raj
Journal: JAMA Neurology (2023)

Importance Knowledge is lacking on the prevalence and prognosis of individuals with a β-amyloid–negative, tau-positive (A−T+) cerebrospinal fluid (CSF) biomarker profile. Objective To estimate the prevalence of a CSF A−T+ biomarker profile and investigate its clinical implications. Design, Setting, and Participants This was a retrospective cohort study of the cross-sectional multicenter University of Gothenburg (UGOT) cohort (November 2019-January 2021), the longitudinal multicenter Alzheimer Disease Neuroimaging Initiative (ADNI) cohort (individuals with mild cognitive impairment [MCI] and no cognitive impairment; September 2005-May 2022), and 2 Wisconsin cohorts, Wisconsin Alzheimer Disease Research Center and Wisconsin Registry for Alzheimer Prevention (WISC; individuals without cognitive impairment; February 2007-November 2020). This was a multicenter study, with data collected from referral centers in clinical routine (UGOT) and research settings (ADNI and WISC). Eligible individuals had 1 lumbar puncture (all cohorts), 2 or more cognitive assessments (ADNI and WISC), and imaging (ADNI only) performed on 2 separate occasions. Data were analyzed on August 2022 to April 2023. Exposures Baseline CSF Aβ42/40 and phosphorylated tau (p-tau)181; cognitive tests (ADNI: modified preclinical Alzheimer cognitive composite [mPACC]; WISC: modified 3-test PACC [PACC-3]). Exposures in the ADNI cohort included [ 18 F]-florbetapir amyloid positron emission tomography (PET), magnetic resonance imaging (MRI), [ 18 F]-fluorodeoxyglucose PET (FDG-PET), and cross-sectional tau-PET (ADNI: [ 18 F]-flortaucipir, WISC: [ 18 F]-MK6240). Main Outcomes and Measures Primary outcomes were the prevalence of CSF AT biomarker profiles and continuous longitudinal global cognitive outcome and imaging biomarker trajectories in A−T+ vs A−T− groups. Secondary outcomes included cross-sectional tau-PET. Results A total of 7679 individuals (mean [SD] age, 71.0 [8.4] years; 4101 male [53%]) were included in the UGOT cohort, 970 individuals (mean [SD] age, 73 [7.0] years; 526 male [54%]) were included in the ADNI cohort, and 519 individuals (mean [SD] age, 60 [7.3] years; 346 female [67%]) were included in the WISC cohort. The prevalence of an A−T+ profile in the UGOT cohort was 4.1% (95% CI, 3.7%-4.6%), being less common than the other patterns. Longitudinally, no significant differences in rates of worsening were observed between A−T+ and A−T− profiles for cognition or imaging biomarkers. Cross-sectionally, A−T+ had similar tau-PET uptake to individuals with an A−T− biomarker profile. Conclusion and Relevance Results suggest that the CSF A−T+ biomarker profile was found in approximately 5% of lumbar punctures and was not associated with a higher rate of cognitive decline or biomarker signs of disease progression compared with biomarker-negative individuals.